Abstract 2108: New analogues of benzyl-isothiourea showed Rb-Raf disruption and anti-cancer activity

Abstract

Abstract The retinoblastoma tumor suppressor protein Rb, is a vital regulator of the mammalian cell cycle which is inactivated by phosphorylation. We had shown that Raf-1 kinase binds and phosphorylates Rb early in the G1 phase facilitating its subsequent phosphorylation by cyclin dependent kinases. This phosphorlation released transcriptionally active E2Fs from Rb to facilitate S-phase entry. Disruption of Rb-Raf protein-protein interaction could prevent proliferation and angiogenesis, leading to inhibition of tumor growth in mouse models. We had earlier identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251) that potently and selectively disrupts Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E or Rb/HDAC interactions. Here, we have made efforts to analyze additional analogues of RRD251; we focused on XW-19B and XW-35B. These compounds inhibited Rb-Raf interaction in vitro and in vivo as shown by ELISA and Immunoprecipitation-Western blot analysis. They also inhibited cell viability, proliferation, migration, invasion, angiogenesis and adherence-independent growth of human lung cancer cell lines A549. XW-19B inhibited tumor growth significantly in human A549 xenograft model in nude mice, compared to control while XW-35B showed certain amount of toxicity to animals at 50MPK. Overall, these results showed that Rb-Raf disruptors XW-19B and XW-35B have potential anticancer activity. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2108. doi:10.1158/1538-7445.AM2011-2108